Summary The newly discovered enzyme, ?/?-hydrolase domain 6 (ABHD6), controls the amount of 2- arachidonoylglycerol (2-AG), the most abundant endocannabinoid (eCB) in the brain. We recently found that in vivo ABHD6 inhibition decreases seizure incidence in several mouse models of epilepsy, and that this therapeutic response does not undergo tolerance nor does it produce overt side effects. These results suggest that ABHD6 inhibition might represent a novel anti-epileptic therapeutic approach. In this R21 grant proposal, we will test the therapeutic efficacy of a novel inhibitor of ABHD6, KT-182, in Scn1a+/- mice, a preclinical mouse model of Dravet Syndrome that accurately mimics this devastating intractable epilepsy that begins in infancy. Our hypothesis is that ABHD6 inhibition will significantly reduce seizure severity in Scn1a+/- mice without producing overt side effect and tolerance. To test this hypothesis, we will address three aims: 1. Effect of ABHD6 inhibition on thermally-induced seizures 2. Effect of ABHD6 inhibition on spontaneous seizures and premature death 3. Effect of ABHD6 inhibition on EEG and neuronal excitability The results gathered through this R21 grant will provide a solid foundation for future research aimed at developing ABHD6 inhibitors as new therapeutics for the treatment of Dravet Syndrome. This research will also increase our basic understanding of the molecular mechanisms by which endogenous 2-AG signalling controls synaptic transmission and seizure incidence.